Indications for PCN Skin Testing

• PCN skin testing is indicated in patients who have a reaction consistent with a possible IgE-mediated mechanism
  • Only 10-15% of patients with a history of PCN reactions are actually allergic to PCN
  • ~80% with PCN allergy lose IgE to PCN after 10 years
  • ~1/3 of patients with a vague history of PCN allergy have positive PCN skin test

• When to do test is controversial:
  • Practice Parameter (2011)
    • May be performed electively—when patients are well and not in immediate need of antibiotic therapy.
      • An argument in favor of elective skin testing is the fact that testing in the acute setting when a patient is ill may be difficult to accomplish in a timely fashion.
    • May be performed when treatment with a PCN is contemplated.
      • An argument in favor of testing at time of need is the potential of skin testing or the subsequent course of PCN (in skin test–negative individuals) to induce resensitization and hence the need to repeat skin testing before each future course.
  • BSACI indications (2011)
    • Patients with a history of an allergic reaction when on multiple drugs, e.g. during anesthesia
    • Patients allergic to multiple antibiotics
    • Patients with an absolute requirement for PCN, e.g. those with central nervous system syphilis, immunodeficiency, post-splenectomy, or with cardiac valve disorders requiring prophylaxis

Testing for Immediate Reactions

• Immediate reactions - occur within 1 hour of drug administration, suggesting an IgE-mediated mechanism

PCN Skin Testing

• SPT and ID with major and 3 minor determinants - perform SPT first, if negative, perform ID
  • Prepen package insert: positive SPT defined as ≥5 mm wheal, positive ID defined as itching and significant increase in size of original (3 mm) blebs to at least 5 mm
    • Perform ID in duplicate, discordant results are considered an ambiguous response that may require further testing
  • Kahn: positive skin test is a change in diameter of ≥3 mm between the 0 min and 15 min reading
    • PCN-allergic patients rarely have a positive SPT
    • Flare response is not required for a positive PCN skin test
    • For the ID, inject a volume sufficient to raise a wheal of approximately 5x5 mm, then measure the diameter of each ID bleb immediately after it is placed
    • A positive reaction to either PCN reagent is a positive test
  • Macy: positive skin test is ≥5 mm than negative control (using 3 mm overly sensitive)

Skin test reagent	Concentrations for SPT and ID Testingspace
Major determinant
Benzylpenicilloyl polylysine (same as PPL, PRE-PEN)space	6 x 10-5 M	European guidelines suggest 5 x 10-5 M 95% of PCN reacts with self-proteins via beta-lactam ring to form benzylpenicilloyl
Minor determinants
Penicillin G (same as benzylpenicillin)nace	10,000 IU/mL (6.27 mg/mL)	Macy: use 0.01 M sodium penicillin G IV solution (equivalent to 3.725 mg/mL or 5941 IU/mL) Kahn: use PfizerPen G (5,000,000 IU) reconstituted with 3.2 mL of saline for a final stock solution of 1,000,000 IU/mL, then add 0.05 mL of this solution to 4.95 mL of saline to get 10,000 IU/mL dilution
Penicilloate	0.01 M (3.75 mg/mL)	In Europe, a minor determinate mixture of penicilloate and penilloate (used undiluted, at 2 x 10^-2 mmol/L) is available
Penilloate	0.01 M (3.32 mg/mL)	In Europe, a minor determinate mixture of penicilloate and penilloate (used undiluted, at 2 x 10^-2 mmol/L) is available
More dilute concentrations may be considered as a starting point for patients with a history of severe anaphylaxis

• Negative predictive value of PCN skin testing with Pre-Pen and all 3 minor determinants - near 100%; PPV 40-100%
• ~10% (6.6-12.5%) of PCN allergic patients have positive skin test only to penicilloate and penilloate
  • NPV of skin testing with penicilloate and penilloate is comparable to NPV of skin testing without them. Based on the literature, skin testing with only Pre-Pen and pen G may have adequate NPV for evaluation of PCN allergy.
  • Alk Abello: "Negative skin test results using Pre-Pen and pen G indicate with a 97% confidence that the patient can be treated without fear of a life threatening reaction with penicillin."
  • If testing is performed with only Pre-Pen and pen G, initial administration of PCN could be done via graded challenge (ie, 1/100 of the dose, followed by the full dose, assuming no reaction occurs during a brief observation period).
• An unstandardized PCN minor determinant mix may be made in the office:
  
  

  Protocol to make PCN Minor Determinant Mix - ACAAI 2009.pdf
  

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(Blanca, Allergy 2009)

Amoxicillin Skin Testing

• Macy: use sodium amoxicillin (A8523 Sigma-Aldrich) at 0.01 molar (3.65 mg/ml)
  
  

  Preparation of Amoxicillin for Skin Testing - Macy 2011.pdf
  

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• Romano: use amoxicillin sodium IV solution (only available in Europe) at 20 mg/mL; if amoxicillin IV solution is not available then ampicillin is a good substitute for amoxicillin when evaluating immediate (but not delayed) reactions, as specific sensitivity to amoxicillin or ampicillin is more likely to occur in delayed reactions

Other β-lactam Skin Testing

• Cephalosporins
• Carbapenems
• Monobactams
• Oxacephems

Specific IgE In-vitro Testing

• Specific IgE to penicilloylpolylysine, penicillin G, penicillin V, amoxicillin, and ampicillin
  • Commercially available, but they are not alternatives to skin testing because they have unknown predictive value (as low as 45%)
  • A positive sIgE test in the context of an appropriate reaction history suggests presence of an IgE-mediated allergy; a negative test does not rule out an IgE-mediated allergy
• Despite its poor performance, sIgE testing may be considered in patients with a history of severe anaphylaxis, either to avoid the risk of skin testing or to confirm negative skin testing before considering a challenge

Confirmatory Oral Challenge

• Following negative skin testing, PCN may be given via graded-dose challenge (if history of reaction is severe) or full dose (if history of reaction is questionable or mild)
  • European guidelines suggest re-testing (i.e. repeat skin testing and challenge) 2-4 weeks after negative PCN skin testing and oral challenge due to concern that the skin testing or challenge will result in resensitization to PCN, particularly in patients with a remote history of severe anaphyactic reaction
  • Macy: single dose of amoxicillin or PCN, typically 250–500 mg PO for an adult or an equivalent weight adjusted dose for young children (alternatively amoxicillin 250 mg PO if ≥4 yo and 125 mg PO if <4) then observe 1 hour
  • Kahn: amoxicillin 500 mg PO, observe 1 hour, but consider graded dose challenge if there is a convincing history

Data Collection Sheet

Testing for Delayed Reactions

• Delayed reactions occur >1 hour after drug administration and are usually due to delayed T-cell mediated hypersensitivity
• Delayed reading of ID test sites may provide evidence of delayed hypersensitivity
• Final step is graded dose challenge (e.g. 1/100th, 1/10th, full dose, with interval of hours-days depending on clinical history)

AX = amoxicillin
MDM = minor determinant mixture

PCN Serum Sickness

• 
  
• 
  
• Cephalosporin (Ceclor) related serum sickness

Cross-reactivity Between β-lactams

	Reaction to cephalosporins	Reaction to carbapenems------	Reaction to monobactams------
Patient allergic to PCN	≤2% Highest risk of cross-reactivity with 1st generation (>2nd>3rd>4th) Some fatal reactions reported	≤1%	None Note that ceftazidime and aztreonam share identical side chain and in-vivo cross-reactivity has been reported
Patient allergic to amoxicillin (but tolerates other PCNs)	12-38% to cefadroxil Should also avoid cefprozil and cefatrizine which have same R-group side chain as cefadroxil
Patent allergic to ampicillin (but tolerates other PCNs)	10% to cephalexin Should also avoid cefaclor, cephradine, cephaloglycin, and loracarbef, which have same R-group side chain as cephalexin

Note regarding serum-sickness:

• All PCNs should probably be avoided if the patient has a history of serum sickness associated with a PCN in the past
• Serum sickness-like reactions to cefaclor and probably other cephalosporins do not prohibit the administration of PCN

Cephalosporin in PCN-allergic Patients

Ampicillin and Amoxicillin

• Nearly identical in structure (amoxicillin has an extra hydroxyl group on its side chain)
• See above for skin test details

Immediate Reactions

• Some patients with immediate-type reactions to amoxicillin and ampicillin have IgE antibodies directed at the R-group side chain (rather than the core penicillin determinants) and are able to tolerate other PCNs.
  • Amoxicillin/ampicillin-specific drug allergic patients (positive skin test to ampicillin/amoxicillin only) make up 2.7-5.8% of PCN skin test positive patients in the US and 25-50% in Europe
• These patients may have skin test results that are positive to a nonirritating concentration of either amoxicillin or ampicillin but test negative to PCN major and minor determinants.
  • Note - the NPV of skin testing with amoxicillin or ampicillin is unknown, and there is no consensus regarding the appropriate concentration that should be used.

Delayed Maculopapular Rashes

• Amoxicillin and ampicillin are associated with delayed maculopapular rash in approximately 5-10% of patients.
  • Not an IgE-mediated reaction (not at risk of a life-threatening immediate reaction to PCN), and in many cases require the presence of a viral infection or other underlying illness.
    • In patients with EBV, up to 95% develop a morbilliform rash when given amoxicillin or ampicillin, and 40-60% develop a rash when given other beta-lactams
    • Other conditions associated with delayed amoxicillin/ampicillin rash: hyperuricemia, taking allopurinol, CLL
  • Most patients will tolerate PCNs other than ampicillin and amoxicillin. If ampicillin or amoxicillin is administered again, the patient may develop a similar eruption or no reaction at all.
    • In 88 pediatric patients with delayed onset (hours-days) maculopapular or urticarial rash during/soon after treatment with a beta-lactam antibiotic, 7% had a reaction when challenged with the same drug 2 months later (and no reactions were more severe than the original reaction)
  • PCN skin testing should be considered even in patients with a history suggestive of delayed amoxicillin/ampicillin-associated maculopapular rashes before a future course of PCN is given
    • If the PCN skin test result is negative, the patient may be treated with PCN (preferably not amoxicillin/ampicillin)
    • If the PCN skin test result is positive, the patient should be given an alternative antibiotic or undergo induction of drug tolerance to PCN

Cross-reactivity

• Between amoxicillin or ampicillin and cephalosporins (see above)

Clavulanic Acid Allergy

• Clavulanic acid is a beta-lactam antibiotic (clavam or oxapenam class) with weak antibacterial activity but is a potent inhibitor of beta-lactamases
• Due to structural differences, its allergenic determinants have little or no cross-reactivity with those generated by benzylpenicillin or amoxicillin.
• Immediate reactions to clavulanic acid component of amoxicillin-clavulanic acid have been reported
• Because clavulanic acid is not available alone, skin testing is performed with amoxicillin/clavulanic acid at 20 mg/mL amoxicillin component and 4 mg/mL clavulanic acid component

PCN Graded Dose Challenge

For History of Immediate Reaction

From Blanca, Allergy 2009

• Note that using >4-5 steps for a graded dose challenge protocol may induce modifications of immune effector cells and therefore induce tolerance in the patient (above table is from European guidelines and uses up to 5 steps)

For History of Delayed Reaction

• 1/100th dose
• 1 week later 1/10th dose
• 1 week later full dose

PCN Desensitization Protocols

Oral (Practice Parameter)

Oral (CDC 2010)

Oral (Kahn)

Intravenous

Resensitization and Repeat Testing

• European guidelines suggest re-testing (i.e. repeat skin testing and challenge) 2-4 weeks after negative PCN skin testing and oral challenge due to concern that the skin testing or challenge will result in resensitization to PCN, particularly in patients with a remote history of severe anaphyactic reaction
• Resensitization rates
  • After skin testing alone (without PCN given): 2.5% of patients with a negative skin test converted to a positive skin test 1 month later
  • After PCN given:
    • In patients with no history of PCN allergy, 8.2% converted to positive skin test 1 month after PCN injection; 0% had reaction with a subsequent dose of PCN
    • In patients with a past history of PCN allergy who later have negative skin test and are then given a course of PCN, rate of resensitization differs by route:
      • PO - Resensitization rare in both pediatric and adult patients, including after repeated courses. Hence, routine repeat penicillin skin testing is not indicated in patients with a history of penicillin allergy who have tolerated 1 or more oral courses of oral penicillin.
        • Consideration may be given to retesting individuals with recent or particularly severe previous reactions.
      • IV - Resensitization more likely; therefore, repeat skin testing before future doses may be warranted.

References